CENTENE
Corporation

Concert Genetics Genetic Testing: Gastroenterologic Disorders (non-
cancerous)
V2.2024
Date of Last Revision: 04/24

Revision log
Coding Implications

CONCERT GENETICS GENETIC

TESTING: GASTROENTEROLOGIC

DISORDERS (NON-CANCEROUS)

See Important Reminder at the end of this policy for important regulatory and legal
information.

OVERVIEW

Genetic testing for gastroenterologic (non-cancerous) disorders may be used to confirm a
diagnosis in a patient who has signs and/or symptoms of a specific gastroenterologic disorder.
Confirming the diagnosis may alter aspects of management and may eliminate the need for
further diagnostic workup. This document addresses genetic testing for common
gastroenterologic (non-cancerous) conditions.

POLICY REFERENCE TABLE

Coding Implications

This clinical policy references Current Procedural Terminology (CPT®). CPT is a registered
trademark of the American Medical Association. All CPT codes and descriptions are copyrighted
2023, American Medical Association. All rights reserved. CPT codes and CPT descriptions are
from the current manuals and those included herein are not intended to be all-inclusive and are
included for informational purposes only. Codes referenced in this clinical policy are for
informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage.
Providers should reference the most up-to-date sources of professional coding guidance prior to
the submission of claims for reimbursement of covered services.

The tests and associated laboratories and CPT codes contained within this document serve only
as examples to help users navigate claims and corresponding criteria; as such, they are not

comprehensive and are not a guarantee of coverage or non-coverage. Please see the Concert
Genetics Platform for a comprehensive list of registered tests.

OTHER RELATED POLICIES

This policy document provides criteria for Genetic Testing for Gastroenterologic Conditions (Non-
Cancerous). Please refer to:

• Genetic Testing: Hereditary Cancer Susceptibility Syndromes for criteria related to
  germline testing for hereditary cancer syndromes, including Lynch/HNPCC syndrome.
• Genetic Testing: Prenatal and Preconception Carrier Screening for criteria related to
  carrier screening in the prenatal, preimplantation, and preconception setting.
• Genetic Testing: Prenatal Diagnosis (via amniocentesis, CVS, or PUBS) and Pregnancy
  Loss for coverage related to prenatal and pregnancy loss diagnostic genetic testing for tests
  intended to diagnose genetic conditions following amniocentesis, chorionic villus sampling
  or pregnancy loss.

• Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and
  Developmental Delay for criteria related to diagnostic genetic testing for conditions
  affecting multiple organ systems.

• Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders for criteria related
  to genetic testing for MTHFR.
• Genetic Testing: General Approach to Genetic and Molecular Testing for criteria related
  to genetic testing for any non-cancerous GI disorders that is not specifically discussed in
  this or another non-general policy.

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CRITERIA

It is the policy of health plans affiliated with Centene Corporation® that the specific genetic
testing noted below is medically necessary when meeting the related criteria:

CELIAC DISEASE

HLA-DQ Genotyping Analysis

1. HLA-DQ2 and HLA-DQ8 variant analysis (81370, 81375, 81376, 81377, 81382, 81383)
   to rule out celiac disease (CD) is considered medically necessary when the
   member/enrollee meets one of the following:

   A. The member/enrollee is being evaluated for celiac disease, AND

   1. Had an inconclusive serology (antibody) result, OR

   2. Had an inconclusive histology (biopsy) result, OR

   3. Started a gluten-free diet before evaluation for celiac disease.

2. HLA-DQ2 and HLA-DQ8 variant analysis (81370, 81375, 81376, 81377, 81382, 81383)
   to rule out celiac disease is considered investigational for all other indications.

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HEREDITARY HEMOCHROMATOSIS

HFE C282Y and H63D Genotyping

1. HFE C282Y and H63D genotyping (81256) to establish a diagnosis of hereditary
   hemochromatosis is considered medically necessary when:

   A. The member/enrollee has abnormal serum iron indices (e.g., elevated serum
   transferrin-iron saturation and/or elevated serum ferritin concentration, indicating
   iron overload), OR

   B. The member/enrollee has a first-degree relative with a diagnosis of hereditary
   hemochromatosis.

2. HFE C282Y and H63D genotyping (81256) to screen for hereditary hemochromatosis in
   the general population is considered investigational for all other indications.

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HEREDITARY PANCREATITIS

Hereditary Pancreatitis Multigene Panel

1. Hereditary pancreatitis multigene panel analysis (81222, 81223, 81404, 81405, 81479) to
   establish a diagnosis of hereditary pancreatitis is considered medically necessary when:

   A. The member/enrollee has personal history of pancreatitis, AND

   B. The member/enrollee meets at least one of the following:

   1. Unexplained episode of acute pancreatitis in childhood (18 years or
      younger), OR

   2. Recurrent (two or more separate, documented) acute attacks of pancreatitis
      for which there is no explanation (anatomical anomalies, ampullary or main
      pancreatic strictures, trauma, viral infection, gallstones, alcohol, drugs,
      hyperlipidemia, etc.), OR

   3. Chronic pancreatitis of unknown cause, particularly with onset before age 35
      years without a history of heavy alcohol use, OR

   4. At least one close relative with recurrent acute pancreatitis, chronic
      pancreatitis of unknown cause, or childhood pancreatitis of unknown cause,
      AND

   C. The panel includes, at a minimum, the following genes: PRSS1, SPINK, CFTR and
   CTRC.

2. Hereditary pancreatitis multigene panel analysis (81222, 81223, 81404, 81405, 81479) to
   establish a diagnosis of hereditary pancreatitis is considered investigational for all other
   indications.

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INFLAMMATORY BOWEL DISEASE

Inflammatory Bowel Disease / Crohn’s Disease Diagnostic Algorithmic Tests

1. Inflammatory bowel disease diagnostic algorithmic tests (81479, 82397, 83520, 86140,
   88342, 88346, 88350) are considered investigational.

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Inflammatory Bowel Disease / Crohn’s Disease Prognostic Algorithmic Tests

1. Inflammatory bowel disease prognostic algorithmic tests (0203U, 81401, 83516, 83520,
   86671, 88346, 88350) are considered investigational.

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Hereditary Inflammatory Bowel Disease / Crohn’s Disease Panel Tests

1. Genetic testing for inflammatory bowel disease (81479, 81321, 81406, 81407), including
   Crohn’s disease, via a multigene panel is considered medically necessary when:

   A. The member/enrollee was diagnosed with infantile-onset inflammatory bowel
   disease (Infantile-IBD) before age 2 years, OR

   B. The member/enrollee was diagnosed with very early onset inflammatory bowel
   disease (VEO-IBD) before age 6 years, AND

   1. At least one of the following:

      a) The member/enrollee has congenital multiple intestinal atresias,
      OR

      b) The member/enrollee has congenital diarrhea, OR

      c) The member/enrollee has a diagnosis of malignancy under age 25,
      OR

      d) The member/enrollee has features of an inborn error of immunity
      such as susceptibility to infections, OR

      e) The member/enrollee has complex autoimmune features, OR

      f) The member/enrollee has a close relative meeting any of the above
      criteria, OR

   2. The member/enrollee is undergoing stem cell transplant, OR

   3. The member/enrollee has a history of multiple intestinal resections.

2. Genetic testing for inflammatory bowel disease (81479, 81321, 81406, 81407), including
   Crohn’s disease, via a multigene panel is considered investigational for all other
   indications.

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Non-invasive Liver Fibrosis Serum Tests

1. Non-invasive liver fibrosis serum tests (0002M, 0003M, 84450, 84460, 85049) to rule out
   liver fibrosis are considered medically necessary when:

   A. The member/enrollee has one of the following:

   1. Nonalcoholic fatty liver disease (NAFLD), OR

   2. Nonalcoholic steatohepatitis (NASH), OR

   3. Type 2 diabetes, OR

   4. Obesity (BMI >25), OR

   5. Abnormal liver function tests, OR

   6. A history of alcohol use, AND

   B. The member/enrollee had previous fibrosis-4 index (FIB-4) testing with a score of
   greater than 1.3.

2. Non-invasive liver fibrosis serum tests (0002M, 0003M, 84450, 84460, 85049) to rule out
   liver fibrosis are considered investigational for all other indications.

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DEFINITIONS

1. Close relatives include first, second, and third degree blood relatives on the same side of
   the family:

   a. First-degree relatives are parents, siblings, and children

   b. Second-degree relatives are grandparents, aunts, uncles, nieces, nephews,
   grandchildren, and half siblings

   c. Third-degree relatives are great grandparents, great aunts, great uncles, great
   grandchildren, and first cousins

2. Infantile-onset inflammatory bowel disease (Infantile-IBD) is defined as clinical
   manifestations and/or receiving the diagnosis when younger than 2 years of age.¹

3. Very early onset inflammatory bowel disease (VEO-IBD) is defined as clinical
   manifestations and/or receiving the diagnosis when younger than 6 years of age.¹

4. Monogenic disorders are health conditions that are caused by mutations in a single gene.

5. Fibrosis-4 (FIB-4) is a blood test that measures the probability of advanced liver fibrosis
   based on AST, ALT, platelets, and age.

¹ Ouahed J, Spencer E, Kotlarz D, et al. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis. 2020 May 12;26(6):820-842. doi: 10.1093/ibd/izz259. PMID: 31833544; PMCID: PMC7216773.

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BACKGROUND AND RATIONALE

Celiac Disease - HLA-DQ Variant Analysis

American College of Gastroenterology (ACG)

The guidelines from the American College of Gastroenterology (2023) addressing the diagnosis
and management of celiac disease (CD) stated that genetic testing for CD- compatible HLA
haplotype is not required for diagnosis in all cases but may be helpful in selected situations such as
in the context of serology-histology discrepancy. If negative, celiac disease is ruled out. HLA
testing is also central to the approach to CD testing for individuals who have already started a GFD
(gluten free diet) before evaluation; in the presence of a CD-compatible haplotype, a gluten
challenge can be offered. (p. 63-64)

American Gastroenterological Association

A clinical practice update on diagnosis and monitoring of celiac disease (2019) states that HLA
testing has value in its negative predictive value to rule out CD in patients who are seronegative but
have histologic changes or did not have serology at the time of diagnosis. HLA testing may be
reserved for second line evaluation of patients with an equivocal diagnosis (inconclusive serology,
histology or prior gluten free diet).

U.S. Preventive Services Task Force

The US Preventive Service Task Form (2017) released guidelines on screening adults and
children for CD. These guidelines reviewed the use of tTG IgA testing followed by an intestinal
biopsy to screen asymptomatic patients. Genotype testing was not discussed. The overall
conclusion of this review was that the current balance of evidence was insufficient to assess
benefits and harms resulting from screening for CD. (p. 1252)

HEREDITARY HEMOCHROMATOSIS

HFE C282Y and H63D Genotyping

European Molecular Quality Network (EMQN)

Molecular genetic testing for hereditary hemochromatosis (HH) is recognized as a reference test to
confirm the diagnosis of suspected HH or to predict its risk. The vast majority (typically >90%) of
patients with clinically characterized HH are homozygous for the p.C282Y variant in the HFE
gene, referred to as HFE-related HH. (p. 479)

The article includes guidelines, which state the following recommendations for HFE testing
strategies:

• Laboratories providing testing for HFE-associated HH should test for p.C282Y (1A)
• According to local practice, p.H63D can be a considered an optional complementary test
  that can be offered sequentially or simultaneously to p.C282Y testing (2C)
• Testing for p.S65C should not be offered

American College of Gastroenterology (ACG)

In 2019, practice guidelines from the ACG made the following statement on genetic testing for
hereditary hemochromatosis (HH):

• We recommend that family members, particularly first-degree relatives, of patients
  diagnosed with HH should be screened for HH (strong recommendation, moderate quality
  of evidence).
• Selective screening of first-degree relatives of patients affected with type1 HH is suggested.
  Studies of patients with HH and their families have demonstrated that most homozygous
  relatives of probands demonstrate biochemical and clinical expression of the disease, not
  only due to the presence of the genetic mutation but also shared environmental factors that
  may increase the penetrance of the disease. (p. 1206)
• We recommend that individuals with the H63D or S65C mutation in the absence of C282Y
  mutation should be counseled that they are not at increased risk of iron overload
  (conditional recommendation, very low quality of evidence). (p. 1208)

The ACG goes on to explain that there is evidence of cost-effectiveness of screening spouses of
HH patients, as well as cost-effectiveness of genetic testing for children of HH patients when
compared to serum screening (p. 1206).

Additionally, the ACG published a suggested algorithm for diagnosis and treatment in their 2019
practice guidelines. This algorithm includes evaluating a patient’s serum transferrin iron saturation
(TS) and serum ferritin (SF), and indicates HFE genotyping if TS is 45% or greater, and/or SF is
elevated (p. 1212).

GeneReviews-HFE Hemochromatosis

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes
through a rigorous editing and peer review process before being published online.

They point out the following regarding transferring-iron saturation (TS) levels in hereditary
hemochromatosis (in the Clinical Characteristics section, Clinical Description-Heterozygotes):

Concert Genetics Genetic Testing: Gastroenterologic Disorders (non-
cancerous)
V2.2024
Date of Last Revision: 04/24

Although a threshold TS of 45% may be more sensitive than higher values for detecting
HFE hemochromatosis, TS of 45% may also identify heterozygotes who are not at risk of
developing other clinical abnormalities.

**Hereditary Pancreatitis Multigene Panel**

American College of Gastroenterology

In 2013, the American College of Gastroenterology issued guidelines on management of acute
pancreatitis and included the following statement: “Genetic testing may be considered in young
patients (younger than 30 years old) if no cause [of acute pancreatitis] is evident, and a family
history of pancreatic disease is present (conditional recommendation, low quality of evidence).” (p.
1402)

In 2020, the American College of Gastroenterology Clinical Guideline: Chronic pancreatitis (CP)
recommended genetic testing in patients with clinical evidence of a pancreatitis-associated disorder
or possible CP in which the etiology is unclear, especially in younger patients. At minimum,
patients with idio-pathic CP should be evaluated for PRSS1, SPINK1, CFTR, and CTRC gene
mutation analysis, although more extended panels with over a dozen susceptibility and modifier
genes, hyper- triglyceridemia genes, and pharmacogenetics are available. (p. 325 and 330)

American Pancreatic Association

In 2014, the American Pancreatic Association published Practice Guidelines in Chronic
Pancreatitis: Evidence-Based Report on Diagnostic Guidelines. A classification guideline for the
etiology of chronic pancreatitis (CP) includes genetic mutations in PRSS1, CFTR, SPINK1, and
others. (p. 7)

GeneReviews - Pancreatitis Overview

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes
through a rigorous editing and peer review process before being published online.

According to GeneReviews, the evaluation of an at-risk individual for chronic pancreatitis
should begin with the first episode of acute pancreatitis, after common causes such as gallstone,
trauma, hypertriglyceridemia or hypercalcemia have been ruled out.

Molecular genetic testing for hereditary pancreatitis is indicated in a proband with pancreatitis
and at least one of the following:
- An unexplained documented episode of acute pancreatitis in childhood

Concert Genetics Genetic Testing: Gastroenterologic Disorders (non- cancerous) V2.2024 Date of Last Revision: 04/24

Note: For Medicaid member/enrollees, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.

Note: For Medicare member/enrollees, to ensure consistency with the Medicare National Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs and LCDs and Medicare Coverage Articles should be reviewed prior to applying the criteria set forth in this clinical policy. Refer to the CMS website at http://www.cms.gov for additional information.

©2018 Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene® and Centene Corporation® are registered trademarks exclusively owned by Centene Corporation.

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